POS0465 UNSUPERVISED CLUSTERING ANALYSIS OF THE SERUM PROTEOME IDENTIFIES SYSTEMIC LUPUS ERYTHEMATOSUS PATIENTS WITH DISTINCTIVE DISEASE SEVERITY AND LUPUS NEPHROPATHY
Authors: C. Lopez-Pedrera, M. Á. Aguirre-Zamorano, L. Muñoz-Barrera, I. Sanchez-Pareja, F. U. Pilar, M. C. Ábalos-Aguilera, N. Barbarroja Puerto, E. Collantes Estevez, R. Ortega Castro, C. Perez-Sanchez
Journal: Annals of the Rheumatic Diseases (2022)

Background Systemic lupus erythematosus (SLE) is a remarkably heterogeneous autoimmune disease. Despite great efforts, our knowledge of serum protein patterns in severe SLE phenotypes is still limited. Objectives This study investigated the serum proteomic profile of SLE, in order to identify relevant clinical patterns. Methods Proximity extension immunoassay (PEA, Olink) was used to assess the serum levels of one hundred and eighty-four inflammation and organ damage-related proteins in patients with SLE (n = 72) and age-matched healthy donors (HD) (n = 18). In parallel, an extensive clinical and analytical profile of recruited subjects was performed. To evaluate the contribution of molecular profiles to the disease severity, unsupervised clustering analyses were developed. Gene ontology enrichment analysis were also carried out to interrogate the biological meaning associated with the molecular signatures identified. Results Several circulating proteins related to inflammation and organ damage were coordinately altered in the serum of SLE patients in relation to HD. Unsupervised clustering analyses differentiated 2 patients clusters presenting different proteomic profiles. Clinically, although no differences were found in terms of age or disease duration, patients belonging to cluster 1 were characterized by a significantly higher status of disease activity (SLEDAI &gt; 6) and prevalence of positivity for anti-ENA and anti-dsDNA antibodies than patients belonging to cluster 2, along with preponderance of patients with biopsy-diagnosed lupus nephritis (LN), abnormal creatinine and proteinuria. Twenty-three serum proteins were found deregulated between clusters. Interestingly, in parallel to well-recognized inflammatory cytokines, chemokines and regulatory proteins of leukocyte activity [Interferon (IFN)-gamma, interleukin (IL)-15RA, IL-20, sCD40, macrophage colony-stimulating factor-1 (CSF-1), leukemia-inhibitory factor receptor (LIF-R), monocyte chemotactic protein (MCP)-1, MCP-4, C-C motif chemokine (CCL)-4, C-X-C motif chemokine (CXCL)-5, CXCL-6, metalloproteinase (MMP)-1, programmed cell-death ligand (PDL)-1, eukaryotic translation initiation factor 4E-bindign protein 1 (4E-BP1)], a number of key proteins involved in renal damage, not previously reported in serum from SLE, were further found significantly deregulated in patients belonging to cluster 1 when compared with cluster 2 (kidney injure molecule 1 (KIM1), Linker for activation of T-cells family member-2 (LAT2), C-type natriuretic peptide (NPPC), Erbin-2 interacted protein (ERBB2IP)]. Conclusion 1) This highly sensitive proteomic analysis in the serum of SLE identified molecular patterns distinguishing patients with high disease activity and active LN, and including several novel candidate proteins, whose exact role and suitability as biomarkers in SLE deserve further investigation. 2) Combination of novel and traditional disease-specific biomarkers may improve diagnosis and management of SLE. Acknowledgements Supported by ISCIII (PI21/005991 and RICOR-RD21/0002/0033) co-financed by FEDER. Disclosure of Interests None declared.